Project Summary/Abstract It is well-established that human cancer has a substantial heritable component. However, studies have thus far only been able to pinpoint a portion of the germline contribution. The hypothesis underpinning this proposal is that genes and alleles that contribute to cancer susceptibility may be revealed using clues from the somatic genome. Specifically, the focus of the project will be to develop a battery of statistical tests that will query large sequencing data sets from patient paired tumor-normal genomes for signals of synergy between the genomic variants in the two genomes. As part of the proposed work, the project will focus on myeloid malignancy to demonstrate the system's efficacy. Toward this end, the project will pursue three Specific Aims: 1. Develop and apply statistical tests to paired whole-exome data from thousands of myeloid malignancy patients to identify genes/alleles that show signals of germline-somatic synergy. a) Query for genes in which germline and somatic events co-occur statistically frequently b) Query for genes in which germline and somatic events are statistically mutually exclusive c) Identify genes in which disruptive germline alleles are preferentially promoted over wild-type in chromosomal allelic imbalance events 2. Query germline DNA and tumor expression data for genes expressing the variant germline allele over wild-type in the tumor. 3. Expand findings in Aims 1 and 2 to a case-control study. Large in-house, public, and collaborator genomic data sets from thousands of patients will be used to statistically assess germline-somatic synergy. Genes showing such signals of synergy will then be subjected to a large case- control study, under the hypothesis that the genes/alleles identified using clues from the somatic genome will emerge as disease susceptibility loci. Ultimately, identifying inherited risk variants would have profound implications for diagnostics, clinical management, and counseling. A panel of known susceptibility variants could be incorporated into screening assays, which would serve as tools to inform physicians and their patients of elevated risk. This could result in a higher level of surveillance, enabling early detection and more informed counselling for families carrying the risk variants. Additionally, researchers would have a better picture of the gene and pathway disruptions that lead to tumor development and resistance, eventually having the potential of finding new druggable targets for these diseases, yielding new therapeutics.